{"gene":"ATP6V1B1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2000,"finding":"Mutations in ATP6V1B1, encoding the B1 subunit of the renal alpha-intercalated cell apical H+-ATPase, cause autosomal recessive distal renal tubular acidosis (rdRTA) with sensorineural deafness, establishing ATP6V1B1 as a critical component of apical H+ secretion in collecting duct alpha-intercalated cells.","method":"Linkage analysis and mutational analysis in rdRTA kindreds; loss-of-function mutations identified in ATP6V1B1","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 — replicated across multiple independent cohorts and labs, genotype-phenotype correlation established","pmids":["12414817","12579397","12500243"],"is_preprint":false},{"year":2003,"finding":"Murine Atp6v1b1 encodes a 513-amino acid B1 subunit with 93% identity to human ATP6V1B1; it is expressed in kidney and testis, and localizes to intercalated cells of the cortical and medullary collecting duct by Northern blotting and immunolocalization.","method":"Molecular cloning, Northern blotting, immunolocalization in mouse kidney; chromosomal mapping","journal":"Gene","confidence":"High","confidence_rationale":"Tier 2 — direct subcellular localization by immunostaining with functional context (acid secretion in intercalated cells)","pmids":["14585495"],"is_preprint":false},{"year":2018,"finding":"In Atp6v1b1 knockout mice, loss of the B1 subunit impairs urinary acidification, and heterozygous Atp6v1b1+/- mice develop a mild incomplete distal RTA under acid load; compensatory downregulation of pendrin occurs specifically in collecting duct of knockout mice, and subcellular localization of a4 and B2 H+-ATPase subunits is unchanged across genotypes.","method":"Atp6v1b1+/+, +/-, and -/- mouse models; HCl acid-loading; renal membrane fractionation; immunolocalization of H+-ATPase subunits","journal":"Cellular physiology and biochemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined physiological and molecular phenotype; multiple orthogonal methods","pmids":["29843146"],"is_preprint":false},{"year":2023,"finding":"In non-type A (alkali-secreting) intercalated cells, the B1 H+-ATPase subunit is required for driving pendrin (Cl-/HCO3- exchanger) activity and for the renal defense against alkalosis; Atp6v1b1 knockout mice show impaired pendrin expression and activity, blunted β2-adrenergic stimulation of pendrin, strongly reduced basolateral H+-ATPase activity, and impaired assembly of V0 and V1 H+-ATPase domains as shown by ligation assays.","method":"Atp6v1b1-/- mouse model; ex vivo microperfused cortical collecting duct assays; alkali load and furosemide treatment protocols; ligation assays for H+-ATPase subunit assembly; immunostaining","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KO mouse, microperfusion, assembly assays, pharmacological challenge) in single rigorous study","pmids":["37990364"],"is_preprint":false},{"year":2017,"finding":"Atp6v1b1 mutant mice on the MRL background exhibit profound hearing impairment associated with enlarged endolymphatic compartments of the inner ear and alkaline urine without overt metabolic acidosis, demonstrating that ATP6V1B1 is required for endolymph pH homeostasis in the inner ear; the hearing phenotype is modulated by strain-specific genetic modifiers mapping to chromosome 13.","method":"Spontaneous Atp6v1b1 mutant (vtx) mice on MRL background; ABR threshold measurements; backcross linkage analysis; comparison to B6 background knockout mice","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — in vivo genetic model with defined inner ear and renal phenotypes; genetic modifier mapping","pmids":["28934385"],"is_preprint":false},{"year":2020,"finding":"ATP6V1B1 knockout in HER2+ breast cancer cells (SKBR3 and JIMT-1) using CRISPR/Cas9 significantly lowers intracellular pH, causes granzyme accumulation without cytotoxicity, and reduces susceptibility to antibody-dependent cellular cytotoxicity (ADCC), demonstrating that ATP6V1B1-dependent vacuolar ATPase activity maintains cytoplasmic pH permissive for granzyme bioactivity.","method":"CRISPR/Cas9 knockout; intracellular pH measurement; granzyme dynamics analysis; ADCC assays in HER2+ cancer cell lines","journal":"Cancer immunology, immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with functional ADCC and pH readouts, single lab study","pmids":["33000417"],"is_preprint":false},{"year":2021,"finding":"Several exonic variants in ATP6V1B1 (c.368G>T, p.Gly123Val; c.370C>T, p.Arg124Trp; c.484G>T, p.Glu162*; c.1102G>A, p.Glu368Lys) cause complete or incomplete exon skipping by disrupting exonic splicing enhancers or interfering with splice site recognition, as demonstrated by minigene splicing assay.","method":"Minigene splicing assay; bioinformatics splice prediction; RT-PCR","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — functional in vitro minigene assay demonstrating mechanistic effect of specific variants on splicing","pmids":["34157794"],"is_preprint":false},{"year":2024,"finding":"ATP6V1B1 promotes ovarian cancer cell proliferation, migration, and invasion in vitro, and tumor growth in vivo; knockdown increases cisplatin sensitivity; mechanistic studies showed ATP6V1B1 regulates activation of the mTOR/autophagy pathway.","method":"Gain- and loss-of-function experiments; in vivo tumor xenograft; mTOR/autophagy pathway analysis","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 — single lab, pathway placement based on downstream readouts without direct biochemical reconstitution","pmids":["38735913"],"is_preprint":false},{"year":2025,"finding":"shRNA-mediated knockdown of ATP6V1B1 in primary monocyte-derived dendritic cells increases HIV-1 entry, associated with changes in endosomal pH and impaired fluid-phase endocytosis and phagocytosis, indicating that ATP6V1B1-dependent endosomal acidification restricts HIV-1 productive infection in dendritic cells.","method":"shRNA knockdown screen in primary MDDCs; HIV-1 infection assay with Vpx-VLPs; endocytosis and phagocytosis assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — functional KD with defined viral entry and endocytosis phenotype, though mechanistic detail is partial","pmids":["40029073"],"is_preprint":false}],"current_model":"ATP6V1B1 encodes the B1 subunit of the vacuolar H+-ATPase (V-ATPase), which localizes to the apical membrane of acid-secreting type A intercalated cells and to both apical and basolateral membranes of alkali-secreting non-type A intercalated cells in the kidney collecting duct, where it drives H+ secretion required for urinary acidification, supports pendrin-mediated HCO3- secretion during alkalosis, and maintains endolymph pH homeostasis in the inner ear; loss-of-function mutations cause distal renal tubular acidosis with sensorineural hearing loss, while the subunit also regulates intracellular/endosomal pH in non-renal contexts including cancer cells and dendritic cells."},"narrative":{"teleology":[{"year":2000,"claim":"Identification of ATP6V1B1 as the disease gene for autosomal recessive distal renal tubular acidosis with sensorineural deafness established the B1 subunit as a non-redundant component of renal acid secretion and inner ear ion homeostasis.","evidence":"Linkage analysis and mutational screening in multiple rdRTA kindreds","pmids":["12414817","12579397","12500243"],"confidence":"High","gaps":["The molecular mechanism by which B1 loss impairs inner ear function was not resolved","Compensation by the B2 isoform was not assessed","No animal model existed to dissect renal vs. otic phenotypes"]},{"year":2003,"claim":"Cloning and tissue-level mapping of murine Atp6v1b1 confirmed restricted expression in kidney intercalated cells and testis, providing an animal system to study B1 function.","evidence":"Molecular cloning, Northern blotting, and immunolocalization in mouse kidney","pmids":["14585495"],"confidence":"High","gaps":["Functional consequences of B1 loss in vivo were not yet tested","Expression in non-renal, non-testicular tissues was not systematically examined"]},{"year":2017,"claim":"A spontaneous Atp6v1b1 mutant mouse demonstrated that B1 is required for endolymph pH homeostasis and that the severity of hearing loss is governed by strain-specific genetic modifiers, explaining variable penetrance of deafness in human patients.","evidence":"ABR thresholds, inner ear morphology, and backcross linkage analysis in MRL-background vtx mutant mice versus B6 knockouts","pmids":["28934385"],"confidence":"High","gaps":["The modifier gene(s) on chromosome 13 were not identified","Whether endolymphatic pH change directly damages hair cells or acts indirectly was not resolved"]},{"year":2018,"claim":"Atp6v1b1 knockout and heterozygous mice under acid load revealed that even partial B1 loss impairs urinary acidification, and that compensatory downregulation of pendrin occurs without redistribution of other V-ATPase subunits, indicating non-redundancy of B1 in acid-secreting intercalated cells.","evidence":"Atp6v1b1+/+, +/−, and −/− mice with HCl acid loading; renal membrane fractionation and immunolocalization","pmids":["29843146"],"confidence":"High","gaps":["Whether B2 partially compensates at the functional level was not quantified","The mechanism linking B1 loss to pendrin downregulation in type A cells was unclear"]},{"year":2020,"claim":"CRISPR knockout of ATP6V1B1 in HER2⁺ breast cancer cells showed that B1-dependent V-ATPase activity maintains intracellular pH permissive for granzyme bioactivity, extending the functional relevance of B1 beyond kidney and ear to tumor immune evasion.","evidence":"CRISPR/Cas9 KO in SKBR3 and JIMT-1 cells; intracellular pH measurement; ADCC assays","pmids":["33000417"],"confidence":"Medium","gaps":["Whether B1 is normally expressed at physiologically relevant levels in breast cancer tissue in vivo is unclear","Direct biochemical link between pH change and granzyme inactivation was not reconstituted"]},{"year":2021,"claim":"Minigene assays demonstrated that several exonic ATP6V1B1 variants cause disease not through missense effects but by disrupting exonic splicing enhancers, revealing an underappreciated mutational mechanism in rdRTA pathogenesis.","evidence":"Minigene splicing assays and RT-PCR for four exonic variants","pmids":["34157794"],"confidence":"Medium","gaps":["Splicing effects were shown in heterologous minigene systems, not patient-derived cells","Impact on V-ATPase assembly and proton transport was not measured"]},{"year":2023,"claim":"Studies in non-type A intercalated cells resolved that B1 is essential not only for apical acid secretion but also for basolateral V-ATPase assembly and pendrin-mediated bicarbonate secretion during alkalosis, fundamentally expanding the role of B1 to alkali defense.","evidence":"Atp6v1b1−/− mice with alkali loading; ex vivo microperfused collecting ducts; proximity ligation assays for V0–V1 assembly","pmids":["37990364"],"confidence":"High","gaps":["Whether B1 directly facilitates V0–V1 assembly or acts indirectly through scaffolding interactions was not determined","Relevance of this basolateral role to inner ear pathology is unknown"]},{"year":2025,"claim":"Knockdown of ATP6V1B1 in primary dendritic cells increased HIV-1 entry by altering endosomal pH and impairing endocytosis, demonstrating a role for B1-dependent acidification in innate antiviral restriction.","evidence":"shRNA knockdown in monocyte-derived dendritic cells; HIV-1 infection, endocytosis, and phagocytosis assays","pmids":["40029073"],"confidence":"Medium","gaps":["Whether this reflects physiological B1 expression levels in dendritic cells in vivo is unknown","The specific endosomal compartment affected was not identified"]},{"year":null,"claim":"The structural basis of B1 versus B2 isoform-specific functions, the identity of genetic modifiers controlling hearing loss penetrance, and the mechanism by which B1 loss alters V0–V1 assembly remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of B1-containing V-ATPase holoenzyme exists","Chromosome 13 modifier gene(s) for hearing loss have not been identified","Direct protein–protein interactions mediating B1-dependent V0–V1 assembly are uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5,8]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,2,3]}],"complexes":["V-ATPase"],"partners":["ATP6V0A4","ATP6V1B2","SLC26A4"],"other_free_text":[]},"mechanistic_narrative":"ATP6V1B1 encodes the B1 catalytic subunit of the vacuolar H⁺-ATPase (V-ATPase), functioning as an essential driver of proton secretion in specialized epithelial cells of the kidney collecting duct and inner ear. In the kidney, B1 is required both for apical H⁺ secretion in acid-secreting type A intercalated cells and for basolateral V-ATPase assembly and pendrin-dependent HCO₃⁻ secretion in non-type A intercalated cells, as demonstrated by knockout mice that exhibit impaired urinary acidification under acid load and blunted defense against alkalosis [PMID:29843146, PMID:37990364]. In the inner ear, loss of ATP6V1B1 disrupts endolymph pH homeostasis, causing enlarged endolymphatic compartments and sensorineural hearing loss, a phenotype modulated by strain-specific genetic modifiers [PMID:28934385]. Autosomal recessive loss-of-function mutations in ATP6V1B1 cause distal renal tubular acidosis with sensorineural deafness in humans [PMID:12414817]."},"prefetch_data":{"uniprot":{"accession":"P15313","full_name":"V-type proton ATPase subunit B, kidney isoform","aliases":["Endomembrane proton pump 58 kDa subunit","Vacuolar proton pump subunit B 1"],"length_aa":513,"mass_kda":56.8,"function":"Non-catalytic subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (PubMed:16769747). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (PubMed:32001091). Essential for the proper assembly and activity of V-ATPase (PubMed:16769747). In renal intercalated cells, mediates secretion of protons (H+) into the urine thereby ensuring correct urinary acidification (PubMed:16769747). Required for optimal olfactory function by mediating the acidification of the nasal olfactory epithelium (By similarity)","subcellular_location":"Apical cell membrane; Basolateral cell membrane","url":"https://www.uniprot.org/uniprotkb/P15313/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATP6V1B1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ATP6V1B1","total_profiled":1310},"omim":[{"mim_id":"617631","title":"IQ DOMAIN-CONTAINING PROTEIN E; IQCE","url":"https://www.omim.org/entry/617631"},{"mim_id":"605239","title":"ATPase, H+ TRANSPORTING, LYSOSOMAL, V0 SUBUNIT A, ISOFORM 4; ATP6V0A4","url":"https://www.omim.org/entry/605239"},{"mim_id":"604592","title":"T CELL IMMUNE REGULATOR 1; TCIRG1","url":"https://www.omim.org/entry/604592"},{"mim_id":"602722","title":"RENAL TUBULAR ACIDOSIS, DISTAL, 3, WITH OR WITHOUT SENSORINEURAL HEARING LOSS; DRTA3","url":"https://www.omim.org/entry/602722"},{"mim_id":"267300","title":"RENAL TUBULAR ACIDOSIS, DISTAL, 2, WITH PROGRESSIVE SENSORINEURAL HEARING LOSS; DRTA2","url":"https://www.omim.org/entry/267300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear membrane","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":128.7},{"tissue":"salivary gland","ntpm":131.8}],"url":"https://www.proteinatlas.org/search/ATP6V1B1"},"hgnc":{"alias_symbol":["VATB","RTA1B","Vma2"],"prev_symbol":["VPP3","ATP6B1"]},"alphafold":{"accession":"P15313","domains":[{"cath_id":"2.40.10.170","chopping":"38-112","consensus_level":"high","plddt":90.9233,"start":38,"end":112},{"cath_id":"3.40.50.12240","chopping":"117-211_218-400","consensus_level":"high","plddt":91.3398,"start":117,"end":400},{"cath_id":"-","chopping":"409-499","consensus_level":"high","plddt":91.5835,"start":409,"end":499}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P15313","model_url":"https://alphafold.ebi.ac.uk/files/AF-P15313-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P15313-F1-predicted_aligned_error_v6.png","plddt_mean":86.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATP6V1B1","jax_strain_url":"https://www.jax.org/strain/search?query=ATP6V1B1"},"sequence":{"accession":"P15313","fasta_url":"https://rest.uniprot.org/uniprotkb/P15313.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P15313/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P15313"}},"corpus_meta":[{"pmid":"12414817","id":"PMC_12414817","title":"Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss.","date":"2002","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12414817","citation_count":223,"is_preprint":false},{"pmid":"2844751","id":"PMC_2844751","title":"Isolation of genes encoding the Neurospora vacuolar ATPase. 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European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/23729491","citation_count":21,"is_preprint":false},{"pmid":"34157794","id":"PMC_34157794","title":"Identification of seven exonic variants in the SLC4A1, ATP6V1B1, and ATP6V0A4 genes that alter RNA splicing by minigene assay.","date":"2021","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/34157794","citation_count":20,"is_preprint":false},{"pmid":"16433694","id":"PMC_16433694","title":"Molecular investigation and long-term clinical progress in Greek Cypriot families with recessive distal renal tubular acidosis and sensorineural deafness due to mutations in the ATP6V1B1 gene.","date":"2006","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16433694","citation_count":19,"is_preprint":false},{"pmid":"33000417","id":"PMC_33000417","title":"Downregulated ATP6V1B1 expression acidifies the intracellular environment of cancer cells leading to resistance to antibody-dependent cellular cytotoxicity.","date":"2020","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/33000417","citation_count":16,"is_preprint":false},{"pmid":"20233014","id":"PMC_20233014","title":"Novel ATP6V1B1 mutations in distal renal tubular acidosis and hearing loss.","date":"2010","source":"Acta oto-laryngologica","url":"https://pubmed.ncbi.nlm.nih.gov/20233014","citation_count":16,"is_preprint":false},{"pmid":"28934385","id":"PMC_28934385","title":"Hearing loss without overt metabolic acidosis in ATP6V1B1 deficient MRL mice, a new genetic model for non-syndromic deafness with enlarged vestibular aqueducts.","date":"2017","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28934385","citation_count":16,"is_preprint":false},{"pmid":"23923981","id":"PMC_23923981","title":"ATP6V1B1 mutations in distal renal tubular acidosis and sensorineural hearing loss: clinical and genetic spectrum of five families.","date":"2013","source":"Renal failure","url":"https://pubmed.ncbi.nlm.nih.gov/23923981","citation_count":13,"is_preprint":false},{"pmid":"29843146","id":"PMC_29843146","title":"Haploinsufficiency of the Mouse Atp6v1b1 Gene Leads to a Mild Acid-Base Disturbance with Implications for Kidney Stone Disease.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29843146","citation_count":12,"is_preprint":false},{"pmid":"27140593","id":"PMC_27140593","title":"Clinical and molecular findings in three Moroccan families with distal renal tubular acidosis and deafness: Report of a novel mutation of ATP6V1B1 gene.","date":"2016","source":"Current research in translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27140593","citation_count":12,"is_preprint":false},{"pmid":"25517796","id":"PMC_25517796","title":"Mutations in exons 3 and 7 resulting in truncated expression of human ATP6V1B1 gene showing structural variations contributing to poor substrate binding-causative reason for distal renal tubular acidosis with sensorineural deafness.","date":"2015","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/25517796","citation_count":8,"is_preprint":false},{"pmid":"35301649","id":"PMC_35301649","title":"Genetic heterogeneity in GJB2, COL4A3, ATP6V1B1 and EDNRB variants detected among hearing impaired families in Morocco.","date":"2022","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/35301649","citation_count":6,"is_preprint":false},{"pmid":"21614596","id":"PMC_21614596","title":"Why is hypercalciuria absent at diagnosis in some children with ATP6V1B1 mutation?","date":"2011","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/21614596","citation_count":6,"is_preprint":false},{"pmid":"20805693","id":"PMC_20805693","title":"Founder mutations in the ATP6V1B1 gene explain most Cypriot cases of distal renal tubular acidosis: first prenatal diagnosis.","date":"2010","source":"Nephron. 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Is able to replace vma2 in a yeast null mutant.","date":"2006","source":"Journal of bioscience and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/17189165","citation_count":6,"is_preprint":false},{"pmid":"37990364","id":"PMC_37990364","title":"The B1 H + -ATPase ( Atp6v1b1 ) Subunit in Non-Type A Intercalated Cells is Required for Driving Pendrin Activity and the Renal Defense Against Alkalosis.","date":"2023","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/37990364","citation_count":5,"is_preprint":false},{"pmid":"38735913","id":"PMC_38735913","title":"ATP6V1B1 regulates ovarian cancer progression and cisplatin sensitivity through the mTOR/autophagy pathway.","date":"2024","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38735913","citation_count":4,"is_preprint":false},{"pmid":"25498251","id":"PMC_25498251","title":"Investigation of ATP6V1B1 and ATP6V0A4 genes causing hereditary hearing loss associated with distal renal tubular acidosis in Iranian families.","date":"2014","source":"The Journal of laryngology and otology","url":"https://pubmed.ncbi.nlm.nih.gov/25498251","citation_count":4,"is_preprint":false},{"pmid":"31733597","id":"PMC_31733597","title":"ATP6V1B1 recurrent mutations in Algerian deaf patients associated with renal tubular acidosis.","date":"2019","source":"International journal of pediatric otorhinolaryngology","url":"https://pubmed.ncbi.nlm.nih.gov/31733597","citation_count":4,"is_preprint":false},{"pmid":"25579729","id":"PMC_25579729","title":"Distal renal tubular acidosis with nerve deafness secondary to ATP6B1 gene mutation.","date":"2015","source":"Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia","url":"https://pubmed.ncbi.nlm.nih.gov/25579729","citation_count":3,"is_preprint":false},{"pmid":"30558562","id":"PMC_30558562","title":"Novel compound heterozygous ATP6V1B1 mutations in a Chinese child patient with primary distal renal tubular acidosis: a case report.","date":"2018","source":"BMC nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/30558562","citation_count":3,"is_preprint":false},{"pmid":"40029073","id":"PMC_40029073","title":"Impairment of endocytosis-related factors FNBP1L, ARHGAP24, and ATP6V1B1 increases HIV-1 entry into dendritic cells.","date":"2025","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/40029073","citation_count":0,"is_preprint":false},{"pmid":"41503293","id":"PMC_41503293","title":"Distal Renal Tubular Acidosis With Sensorineural Deafness in a Saudi Female: A Case Report of an ATP6V1B1 Mutation in a Consanguineous Family.","date":"2025","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/41503293","citation_count":0,"is_preprint":false},{"pmid":"41897147","id":"PMC_41897147","title":"ATP6V1B1-Associated Inherited Distal Renal Tubular Acidosis in Children: Insights from a Literature Review.","date":"2026","source":"Children (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41897147","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18490,"output_tokens":2360,"usd":0.045435},"stage2":{"model":"claude-opus-4-6","input_tokens":5658,"output_tokens":2251,"usd":0.126848},"total_usd":0.172283,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Mutations in ATP6V1B1, encoding the B1 subunit of the renal alpha-intercalated cell apical H+-ATPase, cause autosomal recessive distal renal tubular acidosis (rdRTA) with sensorineural deafness, establishing ATP6V1B1 as a critical component of apical H+ secretion in collecting duct alpha-intercalated cells.\",\n      \"method\": \"Linkage analysis and mutational analysis in rdRTA kindreds; loss-of-function mutations identified in ATP6V1B1\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated across multiple independent cohorts and labs, genotype-phenotype correlation established\",\n      \"pmids\": [\"12414817\", \"12579397\", \"12500243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Murine Atp6v1b1 encodes a 513-amino acid B1 subunit with 93% identity to human ATP6V1B1; it is expressed in kidney and testis, and localizes to intercalated cells of the cortical and medullary collecting duct by Northern blotting and immunolocalization.\",\n      \"method\": \"Molecular cloning, Northern blotting, immunolocalization in mouse kidney; chromosomal mapping\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization by immunostaining with functional context (acid secretion in intercalated cells)\",\n      \"pmids\": [\"14585495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Atp6v1b1 knockout mice, loss of the B1 subunit impairs urinary acidification, and heterozygous Atp6v1b1+/- mice develop a mild incomplete distal RTA under acid load; compensatory downregulation of pendrin occurs specifically in collecting duct of knockout mice, and subcellular localization of a4 and B2 H+-ATPase subunits is unchanged across genotypes.\",\n      \"method\": \"Atp6v1b1+/+, +/-, and -/- mouse models; HCl acid-loading; renal membrane fractionation; immunolocalization of H+-ATPase subunits\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined physiological and molecular phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"29843146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In non-type A (alkali-secreting) intercalated cells, the B1 H+-ATPase subunit is required for driving pendrin (Cl-/HCO3- exchanger) activity and for the renal defense against alkalosis; Atp6v1b1 knockout mice show impaired pendrin expression and activity, blunted β2-adrenergic stimulation of pendrin, strongly reduced basolateral H+-ATPase activity, and impaired assembly of V0 and V1 H+-ATPase domains as shown by ligation assays.\",\n      \"method\": \"Atp6v1b1-/- mouse model; ex vivo microperfused cortical collecting duct assays; alkali load and furosemide treatment protocols; ligation assays for H+-ATPase subunit assembly; immunostaining\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KO mouse, microperfusion, assembly assays, pharmacological challenge) in single rigorous study\",\n      \"pmids\": [\"37990364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Atp6v1b1 mutant mice on the MRL background exhibit profound hearing impairment associated with enlarged endolymphatic compartments of the inner ear and alkaline urine without overt metabolic acidosis, demonstrating that ATP6V1B1 is required for endolymph pH homeostasis in the inner ear; the hearing phenotype is modulated by strain-specific genetic modifiers mapping to chromosome 13.\",\n      \"method\": \"Spontaneous Atp6v1b1 mutant (vtx) mice on MRL background; ABR threshold measurements; backcross linkage analysis; comparison to B6 background knockout mice\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic model with defined inner ear and renal phenotypes; genetic modifier mapping\",\n      \"pmids\": [\"28934385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ATP6V1B1 knockout in HER2+ breast cancer cells (SKBR3 and JIMT-1) using CRISPR/Cas9 significantly lowers intracellular pH, causes granzyme accumulation without cytotoxicity, and reduces susceptibility to antibody-dependent cellular cytotoxicity (ADCC), demonstrating that ATP6V1B1-dependent vacuolar ATPase activity maintains cytoplasmic pH permissive for granzyme bioactivity.\",\n      \"method\": \"CRISPR/Cas9 knockout; intracellular pH measurement; granzyme dynamics analysis; ADCC assays in HER2+ cancer cell lines\",\n      \"journal\": \"Cancer immunology, immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with functional ADCC and pH readouts, single lab study\",\n      \"pmids\": [\"33000417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Several exonic variants in ATP6V1B1 (c.368G>T, p.Gly123Val; c.370C>T, p.Arg124Trp; c.484G>T, p.Glu162*; c.1102G>A, p.Glu368Lys) cause complete or incomplete exon skipping by disrupting exonic splicing enhancers or interfering with splice site recognition, as demonstrated by minigene splicing assay.\",\n      \"method\": \"Minigene splicing assay; bioinformatics splice prediction; RT-PCR\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional in vitro minigene assay demonstrating mechanistic effect of specific variants on splicing\",\n      \"pmids\": [\"34157794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATP6V1B1 promotes ovarian cancer cell proliferation, migration, and invasion in vitro, and tumor growth in vivo; knockdown increases cisplatin sensitivity; mechanistic studies showed ATP6V1B1 regulates activation of the mTOR/autophagy pathway.\",\n      \"method\": \"Gain- and loss-of-function experiments; in vivo tumor xenograft; mTOR/autophagy pathway analysis\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pathway placement based on downstream readouts without direct biochemical reconstitution\",\n      \"pmids\": [\"38735913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"shRNA-mediated knockdown of ATP6V1B1 in primary monocyte-derived dendritic cells increases HIV-1 entry, associated with changes in endosomal pH and impaired fluid-phase endocytosis and phagocytosis, indicating that ATP6V1B1-dependent endosomal acidification restricts HIV-1 productive infection in dendritic cells.\",\n      \"method\": \"shRNA knockdown screen in primary MDDCs; HIV-1 infection assay with Vpx-VLPs; endocytosis and phagocytosis assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional KD with defined viral entry and endocytosis phenotype, though mechanistic detail is partial\",\n      \"pmids\": [\"40029073\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATP6V1B1 encodes the B1 subunit of the vacuolar H+-ATPase (V-ATPase), which localizes to the apical membrane of acid-secreting type A intercalated cells and to both apical and basolateral membranes of alkali-secreting non-type A intercalated cells in the kidney collecting duct, where it drives H+ secretion required for urinary acidification, supports pendrin-mediated HCO3- secretion during alkalosis, and maintains endolymph pH homeostasis in the inner ear; loss-of-function mutations cause distal renal tubular acidosis with sensorineural hearing loss, while the subunit also regulates intracellular/endosomal pH in non-renal contexts including cancer cells and dendritic cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ATP6V1B1 encodes the B1 catalytic subunit of the vacuolar H⁺-ATPase (V-ATPase), functioning as an essential driver of proton secretion in specialized epithelial cells of the kidney collecting duct and inner ear. In the kidney, B1 is required both for apical H⁺ secretion in acid-secreting type A intercalated cells and for basolateral V-ATPase assembly and pendrin-dependent HCO₃⁻ secretion in non-type A intercalated cells, as demonstrated by knockout mice that exhibit impaired urinary acidification under acid load and blunted defense against alkalosis [PMID:29843146, PMID:37990364]. In the inner ear, loss of ATP6V1B1 disrupts endolymph pH homeostasis, causing enlarged endolymphatic compartments and sensorineural hearing loss, a phenotype modulated by strain-specific genetic modifiers [PMID:28934385]. Autosomal recessive loss-of-function mutations in ATP6V1B1 cause distal renal tubular acidosis with sensorineural deafness in humans [PMID:12414817].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of ATP6V1B1 as the disease gene for autosomal recessive distal renal tubular acidosis with sensorineural deafness established the B1 subunit as a non-redundant component of renal acid secretion and inner ear ion homeostasis.\",\n      \"evidence\": \"Linkage analysis and mutational screening in multiple rdRTA kindreds\",\n      \"pmids\": [\"12414817\", \"12579397\", \"12500243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The molecular mechanism by which B1 loss impairs inner ear function was not resolved\",\n        \"Compensation by the B2 isoform was not assessed\",\n        \"No animal model existed to dissect renal vs. otic phenotypes\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Cloning and tissue-level mapping of murine Atp6v1b1 confirmed restricted expression in kidney intercalated cells and testis, providing an animal system to study B1 function.\",\n      \"evidence\": \"Molecular cloning, Northern blotting, and immunolocalization in mouse kidney\",\n      \"pmids\": [\"14585495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequences of B1 loss in vivo were not yet tested\",\n        \"Expression in non-renal, non-testicular tissues was not systematically examined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"A spontaneous Atp6v1b1 mutant mouse demonstrated that B1 is required for endolymph pH homeostasis and that the severity of hearing loss is governed by strain-specific genetic modifiers, explaining variable penetrance of deafness in human patients.\",\n      \"evidence\": \"ABR thresholds, inner ear morphology, and backcross linkage analysis in MRL-background vtx mutant mice versus B6 knockouts\",\n      \"pmids\": [\"28934385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The modifier gene(s) on chromosome 13 were not identified\",\n        \"Whether endolymphatic pH change directly damages hair cells or acts indirectly was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Atp6v1b1 knockout and heterozygous mice under acid load revealed that even partial B1 loss impairs urinary acidification, and that compensatory downregulation of pendrin occurs without redistribution of other V-ATPase subunits, indicating non-redundancy of B1 in acid-secreting intercalated cells.\",\n      \"evidence\": \"Atp6v1b1+/+, +/−, and −/− mice with HCl acid loading; renal membrane fractionation and immunolocalization\",\n      \"pmids\": [\"29843146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether B2 partially compensates at the functional level was not quantified\",\n        \"The mechanism linking B1 loss to pendrin downregulation in type A cells was unclear\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"CRISPR knockout of ATP6V1B1 in HER2⁺ breast cancer cells showed that B1-dependent V-ATPase activity maintains intracellular pH permissive for granzyme bioactivity, extending the functional relevance of B1 beyond kidney and ear to tumor immune evasion.\",\n      \"evidence\": \"CRISPR/Cas9 KO in SKBR3 and JIMT-1 cells; intracellular pH measurement; ADCC assays\",\n      \"pmids\": [\"33000417\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether B1 is normally expressed at physiologically relevant levels in breast cancer tissue in vivo is unclear\",\n        \"Direct biochemical link between pH change and granzyme inactivation was not reconstituted\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Minigene assays demonstrated that several exonic ATP6V1B1 variants cause disease not through missense effects but by disrupting exonic splicing enhancers, revealing an underappreciated mutational mechanism in rdRTA pathogenesis.\",\n      \"evidence\": \"Minigene splicing assays and RT-PCR for four exonic variants\",\n      \"pmids\": [\"34157794\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Splicing effects were shown in heterologous minigene systems, not patient-derived cells\",\n        \"Impact on V-ATPase assembly and proton transport was not measured\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Studies in non-type A intercalated cells resolved that B1 is essential not only for apical acid secretion but also for basolateral V-ATPase assembly and pendrin-mediated bicarbonate secretion during alkalosis, fundamentally expanding the role of B1 to alkali defense.\",\n      \"evidence\": \"Atp6v1b1−/− mice with alkali loading; ex vivo microperfused collecting ducts; proximity ligation assays for V0–V1 assembly\",\n      \"pmids\": [\"37990364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether B1 directly facilitates V0–V1 assembly or acts indirectly through scaffolding interactions was not determined\",\n        \"Relevance of this basolateral role to inner ear pathology is unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Knockdown of ATP6V1B1 in primary dendritic cells increased HIV-1 entry by altering endosomal pH and impairing endocytosis, demonstrating a role for B1-dependent acidification in innate antiviral restriction.\",\n      \"evidence\": \"shRNA knockdown in monocyte-derived dendritic cells; HIV-1 infection, endocytosis, and phagocytosis assays\",\n      \"pmids\": [\"40029073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether this reflects physiological B1 expression levels in dendritic cells in vivo is unknown\",\n        \"The specific endosomal compartment affected was not identified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of B1 versus B2 isoform-specific functions, the identity of genetic modifiers controlling hearing loss penetrance, and the mechanism by which B1 loss alters V0–V1 assembly remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of B1-containing V-ATPase holoenzyme exists\",\n        \"Chromosome 13 modifier gene(s) for hearing loss have not been identified\",\n        \"Direct protein–protein interactions mediating B1-dependent V0–V1 assembly are uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"complexes\": [\"V-ATPase\"],\n    \"partners\": [\"ATP6V0A4\", \"ATP6V1B2\", \"SLC26A4\"],\n    \"other_free_text\": []\n  }\n}\n```"}